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Mechanisms of Α-Synuclein Induced Synaptopathy in Parkinson’S Disease

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Mechanisms of Α-Synuclein Induced Synaptopathy in Parkinson’S Disease King’s Research Portal DOI: 10.3389/fnins.2018.00080 Document Version Publisher's PDF, also known as Version of record Link to publication record in King's Research Portal Citation for published version (APA): Bridi, J. C., & Hirth, F. (2018). Mechanisms of -Synuclein Induced Synaptopathy in Parkinson's Disease. Frontiers in Neuroscience, 12, 80. DOI: 10.3389/fnins.2018.00080 Citing this paper Please note that where the full-text provided on King's Research Portal is the Author Accepted Manuscript or Post-Print version this may differ from the final Published version. If citing, it is advised that you check and use the publisher's definitive version for pagination, volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you are again advised to check the publisher's website for any subsequent corrections. General rights Copyright and moral rights for the publications made accessible in the Research Portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognize and abide by the legal requirements associated with these rights. •Users may download and print one copy of any publication from the Research Portal for the purpose of private study or research. •You may not further distribute the material or use it for any profit-making activity or commercial gain •You may freely distribute the URL identifying the publication in the Research Portal Take down policy If you believe that this document breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 16. Jun. 2018 REVIEW published: 19 February 2018 doi: 10.3389/fnins.2018.00080 Mechanisms of α-Synuclein Induced Synaptopathy in Parkinson’s Disease Jessika C. Bridi and Frank Hirth* King’s College London, Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, London, United Kingdom Parkinson’s disease (PD) is characterized by intracellular inclusions of aggregated and misfolded α-Synuclein (α-Syn), and the loss of dopaminergic (DA) neurons in the brain. The resulting motor abnormalities mark the progression of PD, while non-motor symptoms can already be identified during early, prodromal stages of disease. Recent studies provide evidence that during this early prodromal phase, synaptic and axonal abnormalities occur before the degenerative loss of neuronal cell bodies. These early phenotypes can be attributed to synaptic accumulation of toxic α-Syn. Under physiological conditions, α-Syn functions in its native conformation as a soluble monomer. However, PD patient brains are characterized by intracellular inclusions of insoluble fibrils. Yet, oligomers and protofibrils of α-Syn have been identified to be Edited by: the most toxic species, with their accumulation at presynaptic terminals affecting Mark P. Burns, several steps of neurotransmitter release. First, high levels of α-Syn alter the size Georgetown University, United States of synaptic vesicle pools and impair their trafficking. Second, α-Syn overexpression Reviewed by: Fu-Ming Zhou, can either misregulate or redistribute proteins of the presynaptic SNARE complex. University of Tennessee Health This leads to deficient tethering, docking, priming and fusion of synaptic vesicles at Science Center, United States the active zone (AZ). Third, α-Syn inclusions are found within the presynaptic AZ, Jiajie Diao, University of Cincinnati, United States accompanied by a decrease in AZ protein levels. Furthermore, α-Syn overexpression *Correspondence: reduces the endocytic retrieval of synaptic vesicle membranes during vesicle recycling. Frank Hirth These presynaptic alterations mediated by accumulation of α-Syn, together impair [email protected] neurotransmitter exocytosis and neuronal communication. Although α-Syn is expressed Specialty section: throughout the brain and enriched at presynaptic terminals, DA neurons are the most This article was submitted to vulnerable in PD, likely because α-Syn directly regulates dopamine levels. Indeed, Neurodegeneration, a section of the journal evidence suggests that α-Syn is a negative modulator of dopamine by inhibiting enzymes Frontiers in Neuroscience responsible for its synthesis. In addition, α-Syn is able to interact with and reduce Received: 05 December 2017 the activity of VMAT2 and DAT. The resulting dysregulation of dopamine levels directly Accepted: 01 February 2018 contributes to the formation of toxic α-Syn oligomers. Together these data suggest a Published: 19 February 2018 vicious cycle of accumulating α-Syn and deregulated dopamine that triggers synaptic Citation: Bridi JC and Hirth F (2018) dysfunction and impaired neuronal communication, ultimately causing synaptopathy and Mechanisms of α-Synuclein Induced progressive neurodegeneration in Parkinson’s disease. Synaptopathy in Parkinson’s Disease. Front. Neurosci. 12:80. Keywords: Parkinson’s disease, synapse, SNARE complex, active zone, dopamine, α-synuclein, synaptopathy, doi: 10.3389/fnins.2018.00080 neurodegeneration Frontiers in Neuroscience | www.frontiersin.org 1 February 2018 | Volume 12 | Article 80 Bridi and Hirth Mechanisms of α-Synuclein Induced Synaptopathy INTRODUCTION including constipation, olfactory dysfunction (hyposmia), sleep disturbance, obesity and depression (Figure 1C; Hawkes et al., Parkinson’s disease (PD) is the second most common 2010; Kalia and Lang, 2015; Mahlknecht et al., 2015). During neurodegenerative disorder after Alzheimer’s disease (AD) the prodromal phase of PD and PD-related disorders, which (Kalia and Lang, 2015). The pathological hallmarks of PD precedes degenerative cell loss, the expression levels of a range are intracellular proteinaceous inclusions called Lewy bodies of proteins involved in synaptic transmission are altered in (LB) and Lewy neurites (LN) that are predominantly formed the prefrontal and cingulate cortex, and SN (Dijkstra et al., of misfolded and aggregated forms of the presynaptic protein 2015; Bereczki et al., 2016; Table 1), suggesting that both non- α-Synuclein (α-Syn), and the loss of dopaminergic (DA) neurons motor and motor symptoms are caused by impaired synaptic in the substantia nigra (SN) (Spillantini et al., 1997; Lang communication. This data indicates that neurodegeneration in and Lozano, 1998a,b). Loss of DA neurons in the SN leads to PD is a dying back-like phenomenon which starts at synaptic marked decrease of dopamine levels in synaptic terminals of the terminals in the striatum and progresses along the nigrostriatal dorsal striatum (Figures 1A,B), ultimately leading to a loss of pathway, ultimately affecting homeostasis and survival of DA cell the nigrostriatal pathway (Cheng et al., 2010). The reduction bodies in the SN (Hornykiewicz, 1998; Calo et al., 2016; Caminiti of striatal dopamine triggers a range of motor symptoms et al., 2017). It is due to these early-onset synaptic alterations including bradykinesia, uncontrollable tremor at rest, postural observed prior to DA neuron loss, PD has also been classified as impairment, and rigidity which together characterize PD as a a synaptopathy (Brose et al., 2010; Schirinzi et al., 2016). movement disorder. The majority of PD cases are sporadic with unknown cause. The onset of PD, however, is considered to commence However, familial cases with autosomal dominant or recessive at least 20 years prior to detectable motor abnormalities, Mendelian inheritance have revealed fundamental insights into when a variety of non-motor symptoms can be observed pathogenic mechanisms underlying PD (Keane et al., 2011; (Hawkes et al., 2010; Kalia and Lang, 2015; Mahlknecht et al., Massano and Bhatia, 2012; Kalia and Lang, 2015). The most 2015). This period is referred to as the prodromal phase commonly identified genetic mutations linked to heritable PD where patients experience a range of non-motor symptoms were found in the genes SNCA and LRRK2, responsible for FIGURE 1 | Midbrain dopaminergic neurons are specifically vulnerable in Parkinson’s disease. (A) The predominant symptoms of Parkinson’s disease (PD) are caused by loss of dopaminergic (DA) neurons in the substantia nigra (SN). According to the dying-back hypothesis, the degeneration of DA neurons is preceded by dysfunction and in turn degeneration of the nigrostriatal pathway, which innervates the caudate nucleus and the putamen that together form the striatum. (B) Compared to healthy controls (left), nigrostriatal degeneration results in the depletion and ultimate loss of the neurotransmitter dopamine on synaptic terminals of striatal neurons (right). (C) The resulting motor symptoms, among others, are usually diagnosed when approximately 30–60% of striatal DA neurons are already lost. However, PD patients can experience non-motors symptoms 20 years before the onset of motor abnormalities in the so-called prodromal phase; these include olfactory dysfunction, sleep disturbances and depression. Frontiers in Neuroscience | www.frontiersin.org 2 February 2018 | Volume 12 | Article 80 Bridi and Hirth Mechanisms of α-Synuclein Induced Synaptopathy TABLE 1 | Alterations of presynaptic proteins seen with α-Syn related proteinopathy in PD and DLB patients and rodent animal models. Protein Modification Species Assay system References Synapsin 1 Down Human Post-mortem tissue from DLB patients Scott et al., 2010 Rat BAC rat model overexpressing
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